Genetic Variant RBMX:p.Tyr281Cys (chrX-136875109-T-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_002139.4(RBMX):c.842A>G(p.Tyr281Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,210,221 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000036 ( 0 hom. 2 hem. )

Consequence

RBMX
NM_002139.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.43

Variant links:

Genes affected

RBMX (HGNC:9910): (RNA binding motif protein X-linked) This gene belongs to the RBMY gene family which includes candidate Y chromosome spermatogenesis genes. This gene, an active X chromosome homolog of the Y chromosome RBMY gene, is widely expressed whereas the RBMY gene evolved a male-specific function in spermatogenesis. Pseudogenes of this gene, found on chromosomes 1, 4, 9, 11, and 6, were likely derived by retrotransposition from the original gene. Alternatively spliced transcript variants encoding different isoforms have been identified. A snoRNA gene (SNORD61) is found in one of its introns. [provided by RefSeq, Sep 2009]

RBMX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32571474).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBMX	NM_002139.4 link	c.842A>G	p.Tyr281Cys	missense_variant	Exon 8 of 9	ENST00000320676.11	NP_002130.2	P38159-1
RBMX	NM_001164803.2 link	c.517A>G	p.Thr173Ala	missense_variant	Exon 6 of 8		NP_001158275.1	P38159-3
RBMX	NR_028476.2 link	n.825A>G		non_coding_transcript_exon_variant	Exon 7 of 8
RBMX	NR_028477.2 link	n.1032A>G		non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBMX	ENST00000320676.11 link	c.842A>G	p.Tyr281Cys	missense_variant	Exon 8 of 9	1	NM_002139.4	ENSP00000359645.3		P38159-1

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112125

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34289

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183262

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67716

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1098096

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363480

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000237

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112125

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34289

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.842A>G (p.Y281C) alteration is located in exon 8 (coding exon 7) of the RBMX gene. This alteration results from a A to G substitution at nucleotide position 842, causing the tyrosine (Y) at amino acid position 281 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Pathogenic

0.55

CADD

Uncertain

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.45

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.33

MetaSVM

Uncertain

0.52

PROVEAN

Benign

0.050

REVEL

Benign

0.10

Sift

Pathogenic

0.0

Sift4G

Benign

0.11

Vest4

0.34

MutPred

0.39

Loss of sheet (P = 0.0054);

MVP

0.76

ClinPred

0.98

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over